A major complication of cancer chemotherapy, antiviral chemotherapy, or exposure to radiation, including cancer radiotherapy, is damage to bone marrow cells or suppression of their function. Specifically, chemotherapy and exposure to ionizing radiation cause damage to hematopoietic stem cells primarily found in the bone marrow and spleen, or destroy hematopoietic progenitor cells, impairing the production of new blood cells (granulocytes, lymphocytes, erythrocytes, monocytes, platelets, etc.). For example, treatment of cancer patients with cyclophosphamide or 5-fluorouracil can result in leukocytes (lymphocytes and (or) granulocytes) being destroyed, thereby increasing the susceptibility of the patients to infection. Accordingly, some cancer patients die of infection or other consequences of hematopoietic failure after chemotherapy or radiotherapy. Chemotherapy agents can also result in subnormal formation of platelets, which generates a propensity to hemorrhage. Similarly, mustard gas poisoning causes damage to the hematopoietic system, leading to susceptibility to injection. Inhibition of erythrocyte production can result in anemia. When surviving bone marrow stem cells cannot grow and differentiate fast enough to replenish the number of white blood cells, the body cannot resist pathogenic infectious organisms. Various pathological conditions, such as neutropenia, including idiopathic forms, are associated with damage to specific elements of the hematopoietic system.
Therefore, bone marrow transplantation or bone marrow stem-cell transplantation has been used to improve hematopoietic disorders caused by bone-marrow damage or loss of bone-marrow function due to pathological conditions associated with loss of hematopoietic function caused by chemicals, radiation, diseases, or other factors, and to facilitate the recovery of hematopoietic function.
Stem cells undergo self-renewal over the lifetime of an individual while producing cells of all systems, thereby maintaining homeostasis unique to the tissue. The functional loss associated with the stress response and aging of stem cells is directly linked to the malfunction of the entire tissue. Further, breakdown of the mechanism of controlling the self-renewal of stem cells promptly promotes tumorigenic transformation of stem cells, leading to the development of cancer. Therefore, for advancement of medical care using stem cells, it is important to analyze and control the self-renewal mechanism of stem cells.
In particular, hematopoietic stem cells (HSCs) undergo self-renewal cell division while producing differentiated cells, thereby maintaining the homeostasis of the hematopoietic system. However, excessive cell division of HSCs induces the accumulation of intracellular oxidative stress, etc., leading to a reduction in self-renewal capacity, i.e., shortening of the life of stem cells.
This finally increases the possibility of destroying the tissue regeneration mechanism. In particular, in bone marrow transplantation for leukemia, etc., the transplanted HSCs must undergo hematopoietic regeneration associated with active proliferative response. This causes a significant burden. Therefore, in order to establish safer and more effective regenerative medicine techniques, it is important to establish a method that can draw out the maximum tissue regeneration potential of stem cells, while as much as possible minimizing the stress caused by the regeneration response of stem cells, and maintaining stem-cell function for a long period of time.
Further, for radical treatment of tumors, it is necessary to transfer tumor stem cells in the resting phase, which react poorly to antitumor agents, to the mitotic phase, thereby increasing the sensitivity of the cells to antitumor agents.
Plasminogen activator inhibitor-1 (hereinafter, “PAI-1”) is a serine protease inhibitor that specifically inhibits tissue plasminogen activator (hereinafter, “tPA”) and urokinase-type plasminogen activator (hereinafter, “uPA”). PAI-1 suppresses plasmin production and inhibits fibrin degradation. Based on tertiary structural differences, PAI-1 is present in an active form that shows PA inhibitory activity and in a latent form that shows no PA inhibitory activity. In plasma, PAI-1 is known to be typically present in a concentration of 20 ng/mL, and produced in hepatocytes, megakaryocytes, and lipocytes in addition to vascular endothelial cells, which are the primary PAI-1 producing cells.
PAI-1 is an acute-phase protein and is thought to be one of the factors that cause ischemic organ dysfunctions in sepsis and disseminated intravascular coagulation syndrome (DIC) through accelerated production due to various cytokines and growth factors. Further, genetic polymorphism due to single-base substitutions in the PAI-1 gene promoter is known, and it has been revealed that plasma PAI-1 concentration increases as a result of such genetic polymorphism.
It has been widely studied and reported that PAI-1 is deeply associated with and acts on renal diseases, such as diabetic nephropathy, chronic kidney disease (CKD), nephrotic syndrome, postrenal renal failure, and pyelonephritis (NPL 1 to NPL 5). In addition, PAI-1 is considered to be associated with the formation and development of pathological conditions of various diseases, such as various thromboses, cancer, diabetes, ocular diseases such as glaucoma and retinopathy, polycystic ovary syndrome, radiation injuries, alopecia (baldness), splenohepatomegaly, and arteriosclerosis (NPL 6 to NPL 11). Further, PAI-1 is also considered to be associated with the control of the diurnal rhythm, which is presumably involved in the formation of vascular endothelial cells and the occurrence of events such as cerebral infarction and myocardial infarction (NPL 12 to NPL 14). For this reason, a compound that inhibits PAI-1 activity is useful as a preventive and treatment agent for various diseases such as thrombosis, cancer, diabetes mellitus, diabetic complications, various kidney diseases, ocular diseases such as glaucoma and retinopathy, polycystic ovary syndrome, alopecia, bone-marrow regeneration, splenomegaly due to extramedullary hematopoiesis, amyloidosis, and arteriosclerosis (NPL 15 and NPL 16). In particular, NPL 14 reports that PAI-1 promotes angiogenesis in the retina, and a PAI-1 inhibitor is therefore considered to be useful as an agent for preventing and treating retinopathy and various other diseases that occur in association with angiogenesis. Further, NPL 17 states that a low-molecular-weight PAI-1 inhibitor inhibits differentiation of adipose cells, thereby inhibiting the development of diet-induced obesity. Therefore, a PAI-1 inhibitor is presumably effective for preventing and treating obesity.
Tissue fibril formation occurs in many tissues and organs such as the lungs, heart, blood vessels, liver, and kidneys. A report has disclosed that the progression of pulmonary fibrosis can be suppressed by the administration of a PA or PAI-1 inhibitor to activate the fibrinolysis system (NPL 18). Therefore, a PAI-1 inhibitor is known to be effective for treating tissue fibrosis, in particular pulmonary fibrosis (NPL 16, NPL 19, and NPL 20). It was recently discovered that the decomposition of A (can be promoted by inhibiting PAI-1; this finding suggests that a PAI-1 inhibitor may be usable as a drug for treating Alzheimer's disease (NPL 21).
However, it was not known that a PAI-1 inhibitor acts on stem cells or a microenvironment called “niche” to activate the stem cells.